1. Field of the Invention
The present invention relates generally to methods for quantitative production and selective recovery of usable quantities of [.sup.18 F]F.sup.- and [.sup.13 N]NO.sub.3.sup.- /NO.sub.2.sup.- from irradiation of low-enriched [.sup.18 O]H.sub.2 O, for radiotracer synthesis for clinical PET imaging.
2. Description of the Related Art
The clinical usefulness of positron emission tomography (PET) studies using [.sup.13 N]ammonia ([.sup.13 N]NH.sub.3) and 1-[.sup.18 F]fluoro-2-deoxy-D-glucose ([.sup.18 F]FDG) is well established. Myocardial imaging in clinical PET using [.sup.13 N]NH.sub.3 to measure blood flow followed in series with [.sup.18 F]FDG to assess tissue glucose uptake, is finding increased use for diagnosing myocardial disease. Schelbert, H. R. and Schwaiger, M., in Phelps, M. E., Mazziotta, J. C. and Schelbert, H. R. (eds.), (1986) Positron Emission Tomography and Autoradiography, Raven Press, New York. Chapter 12. These agents are among the best validated and most widely used PET tracers in humans and will serve as key agents in clinical PET programs for the foreseeable future. As the demand for PET studies increases, cyclotron-PET facilities must find ways to economically provide large quantities of these tracers for clinical use.
Logistical complications arise in protocols requiring more than one agent simultaneously, such as when [.sup.13 N]NH.sub.3 and [.sup.18 F]FDG are required in combination for heart studies. Matters are further complicated by the relatively short half-lives of the .sup.13 N and .sup.18 F isotopes, 10 minutes and 110 minutes, respectively. Studies of this nature can impose enormous time constraints on both cyclotron and hot lab operations to produce and deliver these radiotracers in rapid succession. Such constraints can lead to unnecessary radiation exposure to personnel, particularly if production targets are mounted by hand, to excessive cyclotron usage, and ultimately to longer radiotracer delivery times. Under these circumstances, it is important for isotope production schedules to be flexible and agent syntheses to be simple, reliable and fast.
Mulholland et al. in "Direct Simultaneous Production of [.sup.15 O]Water and [.sup.13 N]Ammonia or [.sup.18 F]Fluoride Ion by 26 MeV Proton Irradiation of a Double Chamber Water Target", Appl. Radiat. Isot., 41(12), 1195-1199 (1990) describe a double liquid chamber target to provide simultaneous production of [.sup.15 O]H.sub.2 O and either .sup.13 N or .sup.18 F using a single proton beam. Proton irradiation of natural water in a first chamber produces [.sup.15 O]H.sub.2 O by the .sup.16 O(p,pn).sup.15 O reaction. The [.sup.15 O]H.sub.2 O is separated from the natural water using a mixed bed of 3:1:1 AG1:AG50:Chelex 100 ion exchange resins (reusable) for in-line purification of the water as it leaves the target.
A second target chamber, also in line with the incident proton beam, is used for the production of either .sup.13 N or .sup.18 F. If .sup.13 N is to be produced, the second chamber contains natural water and the .sup.16 O(p,.alpha.).sup.13 N reaction is employed. Alternatively, if .sup.18 F is desired, the second chamber contains [.sup.18 O]H.sub.2 O and the .sup.18 O(p,n).sup.18 F reaction is employed. Hydrogen gas is used in both the front and rear chambers to suppress boiling and maintain proper target thickness while creating a reducing atmosphere to inhibit oxidation of the target precursors. An in-line anion exchange (AG1) (Cl.sup.-) resin-containing column is used for radiochemical cleanup to produce high yields of sterile, aqueous [.sup.13 N]NH.sub.3 (40-200 mCi; 20 .mu.A) directly in-line from the rear chamber at the same time that the [.sup.15 O]H.sub.2 O is produced in the front chamber. Mulholland et al. report that an AG1 column is effective in removing [.sup.13 N]NO.sub.3.sup.- /NO.sub.2.sup.- contaminants from the [.sup.13 N]NH.sub.3, as well as trace amounts of [.sup.18 F]F.sup.-, produced incidentally due to the .sup.18 O present in natural abundance in the target water (see, Mulholland et al., J. Nucl. Med., 30, 926 (1989)).
Although Mulholland et al. describe the simultaneous production of [.sup.15 O]H.sub.2 O with either [.sup.13 N]NH.sub.3 or [.sup.18 F]F.sup.-, they do not disclose or suggest the simultaneous production and purification of [.sup.13 N]NH.sub.3 and [.sup.18 F]F.sup.- from low-enriched [.sup.18 O]H.sub.2 O. Mulholland et al. use natural [.sup.16 O]H.sub.2 O in the rear target for producing [.sup.13 N]NH.sub.3 directly, and dispose of any trace amounts of .sup.13 N or .sup.18 F anions that might be produced. Alternatively, Mulholland et al. use expensive, highly enriched [.sup.18 O]H.sub.2 O to produce [.sup.18 F]F.sup.- ions. Accordingly, the apparatus and methods described by Mulholland et al. are incapable of producing usable quantities of both .sup.13 N and .sup.18 F radioisotopes from a single irradiation.
Other target and ion separation systems for recovering one of the two isotopes of interest are described in various publications. For example, Mulholland et al., "A Reliable Pressurized Water Target for F-18 Production at High Beam Currents", J. Lab. Cpds. Radiopharm., 26, 192 (1989) is solely directed to the production of .sup.18 F from enriched [.sup.18 O]H.sub.2 O-containing targets; while Mulholland et al., "Direct In-Target Synthesis of Aqueous N-13 Ammonia by Proton Irradiation of Water Under Hydrogen Pressure", J. Nucl. Med., 30, 926 (1989) is solely directed to the production of .sup.13 N[NH.sub.3 ] from natural [.sup.16 O]H.sub.2 O containing targets. Likewise, U.S. Pat. No. 4,752,432 discloses a device and process for production [.sup.13 N]NH.sub.4.sup.+ ion from a .sup.13 C/fluid slurry target. This patent describes the use of a conventional purification column to remove unwanted nitrogen oxides (NO.sub.x.sup.-), yielding the purified [.sup.13 N]NH.sub.4.sup.+ ion aqueous product. The Schlyer et al. article, "Separation of [.sup.18 F]Fluoride from [.sup.18 O]Water Using Anion Exchange Resin", Appl. Radiat. Isot., 41(6), 531-533 (1990) describes the use of a .sup.18 O enriched water target which is bombarded with a proton beam. The method uses an anion exchange resin, Dowex 1X-10, 200-400 mesh in the chloride form which is converted to the hydroxide form. Schlyer et al. also describe using the carbonate form of the resin after similar procedures, rinsing the column with either 0.1M K.sub.2 CO.sub.3 or 0.1M Cs.sub.2 CO.sub.3 solution to elute the .sup.18 F from the column. There is no description in this paper for recovering [.sup.13 N]NO.sub.x.sup.- anions.
Another procedure for recovery of [.sup.18 F]F.sup.- from [.sup.18 O]H.sub.2 O after proton bombardment of a target is described by Alexoff et al., in "Recovery of [.sup.18 F]Fluoride from [.sup.18 O]Water in an Electrochemical Cell", Appl. Radiat. Isot., 40(1), 1-6 (1989). This method only recovers [.sup.18 F]F.sup.- from the [.sup.18 O]H.sub.2 O and does not describe or suggest the production or recovery of .sup.13 N.
The separation of various radioactive isotopes using anion exchange resins is well known. A detailed recitation of such separations is provided by Lavrukhina et al., in "CHEMICAL ANALYSIS OF RADIOACTIVE MATERIALS", Chapter 2 "Theoretical Bases of the Methods of Radiochemical Analysis", 67-175, Iliffe Books, Ltd. London (1967). Specifically, pages 122-126 contain a discussion of the separation of elements using anion exchange chromatography. The discussion is focused towards the use of anion exchange resin such as Dowex-1-X-8 resin to separate various heavy metals and other fission products. Lavrukhina et al. do not describe or suggest the separation of .sup.18 F.sup.-, .sup.13 N.sup.- anions from low-enriched [.sup.18 O]H.sub.2 O. Similarly, U.S. Pat. No. 2,636,044 describes rare earth separations by anion exchange chromatography. The only examples in the patent are for the extraction of radioactive Pm and Eu with a citric acid eluant. In addition, U.S. Pat. No. 3,953,568 describes a method for simultaneously separating radioisotopes of a single element from each other using an anion exchange resin column and a ligand which preferably binds to one of the isotopes. There is no description of separation of different radioisotopes, such as .sup.18 F and .sup.13 N anions from low-enriched [.sup.18 O]H.sub.2 O.
Although other methods and processes are known for the clinical and experimental production of isotopes by proton irradiation, none provides a method for simultaneously producing usable quantities of [.sup.13 N]NH.sub.3 and [.sup.18 F]F.sup.- and the selective isolation and recovery of the isotopes for radiotracer synthesis.
Accordingly, it is a purpose of the invention to provide an improved method for the simultaneous production of .sup.13 N and .sup.18 F isotopes for radiotracer synthesis.
It is also a goal of the invention to provide an improved process for selective extraction and recovery of .sup.13 N and .sup.18 F isotopes for radiotracer synthesis.
It is a further goal of the invention to provide an improved apparatus for simultaneous production of and selective extraction and recovery of usable quantities of .sup.13 N and .sup.18 F isotopes for radiotracer synthesis.
Other purposes and advantages of the present invention will be more fully apparent from the ensuing disclosure and appended claims.